Tumor-associated macrophages (TAMs) exert tumor-promoting effects. There have been reports that estrogen receptors (ERs) are expressed on the infiltrating macrophages of endometriosis, ovarian cancer and lung cancer. However, the role of ERs in macrophages is not well characterized. In this study, we identified that ER alpha (ERα) expression on the macrophages of human endometrial cancer was positively correlated with cancer progression. Conditioned medium from selective ERα agonist-treated M2 macrophages induced the epithelial to mesenchymal transition (EMT) in endometrial cancer cells. However, this effect can be inhibited by ERα antagonist. Here, we showed that macrophages ERα-engaged abundantly produced chemokine (C-C motif) ligand 18 (CCL18), and its expression promoted the invasion of endometrial cancer cells by activating the extracellular signal-regulated kinase 1/2 pathway, whereas suppressing CCL18 abrogated these effects. Furthermore, we identified that CCL18 derived from TAMs upregulated KIF5B expression to promote EMT via activating the PI3K/AKT/mTOR signaling pathway in endometrial cancer. Overall, our findings show how ERα-engaged infiltrating macrophages initiate chronic inflammation and promote the aggressive progression of endometrial cancer cells. ERα-positive TAMs act as drivers of endometrial cancer, which may become a potential therapeutic target.

中文翻译：

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巨噬细胞ERα通过mTOR / KIF5B介导的上皮向间质转化促进子宫内膜癌细胞的侵袭。

肿瘤相关巨噬细胞（TAM）发挥肿瘤促进作用。已有报道，雌激素受体（ER）在子宫内膜异位症，卵巢癌和肺癌的浸润巨噬细胞上表达。但是，ERs在巨噬细胞中的作用尚不明确。在这项研究中，我们确定了人类子宫内膜癌巨噬细胞上的ERα（ERα）表达与癌症进展呈正相关。来自选择性ERα激动剂处理的M2巨噬细胞的条件培养基在子宫内膜癌细胞中诱导了上皮向间充质转化（EMT）。但是，这种作用可以被ERα拮抗剂抑制。在这里，我们发现巨噬细胞ERα参与产生了丰富的趋化因子（CC基序）配体18（CCL18），它的表达通过激活细胞外信号调节激酶1/2途径促进子宫内膜癌细胞的侵袭，而抑制CCL18则消除了这些作用。此外，我们发现，来自TAM的CCL18通过激活PI3K / AKT / mTOR子宫内膜癌来上调KIF5B表达以促进EMT。总体而言，我们的发现表明，与ERα结合的浸润巨噬细胞如何引发慢性炎症并促进子宫内膜癌细胞的侵袭性进展。ERα阳性TAM充当子宫内膜癌的驱动器，可能成为潜在的治疗靶标。我们发现，来自TAM的CCL18通过激活子宫内膜癌中的PI3K / AKT / mTOR信号通路上调了KIF5B表达以促进EMT。总体而言，我们的发现表明，与ERα结合的浸润巨噬细胞如何引发慢性炎症并促进子宫内膜癌细胞的侵袭性进展。ERα阳性TAM充当子宫内膜癌的驱动器，可能成为潜在的治疗靶标。我们发现，来自TAM的CCL18通过激活子宫内膜癌中的PI3K / AKT / mTOR信号通路上调了KIF5B表达以促进EMT。总体而言，我们的发现表明，与ERα结合的浸润巨噬细胞如何引发慢性炎症并促进子宫内膜癌细胞的侵袭性进展。ERα阳性TAM充当子宫内膜癌的驱动器，可能成为潜在的治疗靶标。